Cohesin is an evolutionarily conserved, four-subunit complex that entraps DNA fibres within its ring-shaped structure. It was originally identified and named for its role in mediating sister ...chromatid cohesion, which is essential for chromosome segregation and DNA repair. Increasing evidence indicates that cohesin participates in other processes that involve DNA looping, most importantly, transcriptional regulation. Mutations in genes encoding cohesin subunits and other regulators of the complex have recently been identified in several types of tumours. Whether aneuploidy that results from chromosome missegregation is the major contribution of cohesin mutations to cancer progression is under debate.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cohesin is a complex conserved in evolution that entraps DNA. Originally identified for its role in sister chromatid cohesion, it is currently considered a key player in 3D genome organization. In ...vertebrates, two paralog genes encode two versions of the SA/STAG subunit of cohesin, STAG1 and STAG2. While the existence of two variant complexes has been largely ignored in many cohesin studies, the high frequency of STAG2 mutations in cancer has stirred up the interest in dissecting the unique properties that the STAG proteins confer on cohesin. In this review, we summarize recent progress in our understanding of the functional specificity of cohesin-STAG1 and cohesin-STAG2 with particular emphasis on their contributions to genome organization and gene regulation.
Replicated chromatids are held together from the time they emerge from the replication fork until their separation in anaphase. This process, known as cohesion, promotes faithful DNA repair by ...homologous recombination in interphase and ensures accurate chromosome segregation in mitosis. Identification of cohesin thirty years ago solved a long-standing question about the nature of the linkage keeping together the sister chromatids. Cohesin is an evolutionarily conserved complex composed of a heterodimer of the Structural Maintenance of Chromosomes (SMC) family of ATPases, Smc1 and Smc3, the kleisin subunit Rad21 and a Huntingtin/EF3/PP2A/Tor1 (HEAT) repeat domain-containing subunit named SA/STAG. In addition to mediating cohesion, cohesin plays a major role in genome organization. Cohesin functions rely on the ability of the complex to entrap DNA topologically and in a dynamic manner. Establishment of cohesion during S phase requires coordination with the DNA replication machinery and restricts the dynamic behaviour of at least a fraction of cohesin. Dissolution of cohesion in subsequent mitosis is regulated by multiple mechanisms that ensure that daughter cells receive the correct number of intact chromosomes. We here review recent progress on our understanding of how these processes are regulated in somatic vertebrate cells.
Cohesin in development and disease Remeseiro, Silvia; Cuadrado, Ana; Losada, Ana
Development (Cambridge),
09/2013, Letnik:
140, Številka:
18
Journal Article
Recenzirano
Odprti dostop
Cohesin is a ring-shaped complex, conserved from yeast to human, that was named for its ability to mediate sister chromatid cohesion. This function is essential for chromosome segregation in both ...mitosis and meiosis, and also for DNA repair. In addition, more recent studies have shown that cohesin influences gene expression during development through mechanisms that likely involve DNA looping and interactions with several transcriptional regulators. Here, we provide an overview of how cohesin functions, highlighting its role both in development and in disease.
Two variant cohesin complexes containing SMC1, SMC3, RAD21 and either SA1 (also known as STAG1) or SA2 (also known as STAG2) are present in all cell types. We report here their genomic distribution ...and specific contributions to genome organization in human cells. Although both variants are found at CCCTC-binding factor (CTCF) sites, a distinct population of the SA2-containing cohesin complexes (hereafter referred to as cohesin-SA2) localize to enhancers lacking CTCF, are linked to tissue-specific transcription and cannot be replaced by the SA1-containing cohesin complex (cohesin-SA1) when SA2 is absent, a condition that has been observed in several tumors. Downregulation of each of these variants has different consequences for gene expression and genome architecture. Our results suggest that cohesin-SA1 preferentially contributes to the stabilization of topologically associating domain boundaries together with CTCF, whereas cohesin-SA2 promotes cell-type-specific contacts between enhancers and promoters independently of CTCF. Loss of cohesin-SA2 rewires local chromatin contacts and alters gene expression. These findings provide insights into how cohesin mediates chromosome folding and establish a novel framework to address the consequences of mutations in cohesin genes in cancer.
Structural maintenance of chromosomes (SMC) proteins are chromosomal ATPases, highly conserved from bacteria to humans, that play fundamental roles in many aspects of higher-order chromosome ...organization and dynamics. In eukaryotes, SMC1 and SMC3 act as the core of the cohesin complexes that mediate sister chromatid cohesion, whereas SMC2 and SMC4 function as the core of the condensin complexes that are essential for chromosome assembly and segregation. Another complex containing SMC5 and SMC6 is implicated in DNA repair and checkpoint responses. The SMC complexes form unique ring- or V-shaped structures with long coiled-coil arms, and function as ATP-modulated, dynamic molecular linkers of the genome. Recent studies shed new light on the mechanistic action of these SMC machines and also expanded the repertoire of their diverse cellular functions. Dissecting this class of chromosomal ATPases is likely to be central to our understanding of the structural basis of genome organization, stability, and evolution.
Nuclear waste disposal represents one of the biggest socio-economic challenges of this century and probably for many centuries to come. It is a highly complex issue due to the interrelated technical, ...material, social, economic and political dimensions as well as the real or perceived risks involved. Distrust in technology, institutions, industry and even experts and decision-making processes are some of the reasons for opposition to nuclear waste disposal strategies. Our contribution analyses the dynamics of trust and distrust in Germany over the evolution of the search for a nuclear waste repository site in the last 40 years, identifies major turning points and explores the main factors that shaped trust/distrust relations over time. Site selection conflicts have often provoked 'confidence gaps' and site selection policies depend heavily on relationships based on mutual recognition and trust. We select key factors considered necessary to build trust in institutions and siting selection procedures and review recent changes in the institutional setting, including the establishment of a National Civil Society Board and the attempt to design more participatory procedures. Twenty-one stakeholders and experts were asked to rate some of the identified factors necessary for building trust and whether the measures carried out so far are sufficient to enhance trust in the relevant institutions and procedures and increase public confidence. Without a trust-building process for the siting, development and operation of a risky asset, a short-term attenuation of long-lasting conflicts is unlikely. The legacy of the past still plays an inhibiting role. In addition to expert judgement, evidence was derived from document analysis and participatory observation in the works of the German 'Commission on the Storage of High-level Radioactive Waste' and of the 'National Civil Society Board' as well as of events of regulator and operator.
Cohesin organizes the genome through the formation of chromatin loops. NIPBL activates cohesin's ATPase and is essential for loop extrusion, but its requirement for cohesin loading is unclear. Here ...we have examined the effect of reducing NIPBL levels on the behavior of the two cohesin variants carrying STAG1 or STAG2 by combining a flow cytometry assay to measure chromatin-bound cohesin with analyses of its genome-wide distribution and genome contacts. We show that NIPBL depletion results in increased cohesin-STAG1 on chromatin that further accumulates at CTCF positions while cohesin-STAG2 diminishes genome-wide. Our data are consistent with a model in which NIPBL may not be required for chromatin association of cohesin but it is for loop extrusion, which in turn facilitates stabilization of cohesin-STAG2 at CTCF positions after being loaded elsewhere. In contrast, cohesin-STAG1 binds chromatin and becomes stabilized at CTCF sites even under low NIPBL levels, but genome folding is severely impaired.
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•Massive metabolic reprogramming was unveiled for Haematoccocus reddish cells.•The differential expression of 100s of genes induces this metabolic reprogramming.•bHLH transcription ...factor family is a putative astaxanthin biosynthesis regulator.•Vegetative reddish palmelloid cells are a model for astaxanthin synthesis studies.
Astaxanthin is a valuable and highly demanded ketocarotenoid pigment, for which the chlorophycean microalga Haematococcus pluvialis is an outstanding natural source. Although information on astaxanthin accumulation in H. pluvialis has substantially advanced in recent years, its underlying molecular bases remain elusive. An integrative metabolic and transcriptomic analysis has been performed for vegetative Haematococcus cells, grown both under N sufficiency (green palmelloid cells) and under moderate N limitation, allowing concurrent active cell growth and astaxanthin synthesis (reddish palmelloid cells). Transcriptional activation was noticeable in reddish cells of key enzymes participating in glycolysis, pentose phosphate cycle and pyruvate metabolism, determining the adequate provision of glyceraldehyde 3 phosphate and pyruvate, precursors of carotenoids and fatty acids. Moreover, for the first time, transcriptional regulators potentially involved in controlling astaxanthin accumulation have been identified, a knowledge enabling optimization of commercial astaxanthin production by Haematococcus through systems metabolic engineering.
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